Project Summary This R01 grant is aimed at better understanding the molecular mechanisms by which chronic exposure to drugs of abuse induces long-lasting changes in the brain's reward circuits that contribute to the complex behavioral abnormalities that define an addicted state. Our work focuses on the transcription factor, AFosB, which is induced in the nucleus accumbens (NAc) and other key brain reward regions in response to chronic administration of virtually all drugs of abuse. AFosB is unique in that it accumulates to appreciable levels only after chronic drug exposure and, because of its unusual stability, persists for weeks-months of withdrawal. AFosB is thus one mechanism by which chronic drug exposure can drive long-lasting changes in gene expression that contribute to addiction. Indeed, considerable evidence supports the view that induction of AFosB in NAc mediates a state of heightened reward and motivation that could contribute to aspects of the addiction process. In this requested R37 renewal, we will characterize the precise mechanisms through which AFosB exerts these actions. Using state-of-the-art genome-wide chromatin assays, we will identify the genes in the NAc that are direct targets for AFosB in the context of cocaine and opiate self-administration. Such genes, in turn, provide novel insight into the molecular and cellular basis of drug-induced neural and behavioral plasticity. Interestingly, when AFosB binds to its target genes, it can either activate or repress them. Our hypothesis is that such activation vs. repressive actions are determined by the chromatin milieu of the affected gene. As well, partially non-overlapping genes are regulated by AFosB in NAc in response to the two drugs. Although this is likely mediated in part by the partly distinct subsets of neurons in which the drugs induce AFosB, we once again hypothesize that this specificity is also mediated partly by differences in other chromatin changes that cocaine and opiates induce at specific genes. In addition to exploring AFosB's regulation of target genes, we will also characterize several mechanisms that are crucial in determining the amount and activity of AFosB induced in the NAc. Together, these studies will identify many novel actions of drugs of abuse which can be exploited for the development of improved diagnostic tests and treatments for addiction.